Combined Modality Targeted Therapy of Pancreatic Cancer with Death Receptor

项目总结(见说明)； 这项建议是原孢子赠款中项目2的延续。与这项提议相关的是，我们有 通过体外研究开发了一种抗DRS单抗治疗胰腺癌的方法。 与行业合作伙伴(Daiichi Sankyo)合作的第一阶段和最近完成的第二阶段试验 胰腺癌。我们还发现了一种新的分子(DDX3)，它似乎扮演着重要的角色 在调节抗DRS介导的细胞凋亡方面。在这项建议中，我们将探讨两个策略，以加强 抗DRS单抗治疗胰腺癌的疗效观察 对抗DRS有抵抗力。这两种策略是评估添加抗DR4的单抗试剂或 小分子调节剂的加入导致了细胞凋亡的级联。这两种细胞凋亡调节剂是 被评估的是一种Bcl2家族的抑制剂AT-101和一种LAP家族的抑制剂AT-406。这两个战略将 使用体外分析和原位和转移性胰腺癌模型进行研究 导致了最佳策略的第一阶段试验。此外，我们还将继续研究DDX3和 DRS/DDX3复合体作为肿瘤细胞对死亡受体介导的敏感性/耐药性的生物标志物 抗肿瘤效应，并作为抗DR介导的抗肿瘤效应增强策略的靶点。

PROJECT SUMMARY (See instructions); This proposal is a continuation of Project 2 in the original SPORE grant. Pertinent to this proposal, we have developed an anti-DRS monoclonal antibody therapy for pancreatic cancer through in vitro studies, animal model efficacy and with an industry partner (Daiichi Sankyo), Phase I and recently completed Phase II trials in pancreatic cancer. We have also discovered a novel molecule (DDX3) which appears to play a major role in regulation of anti-DRS mediated apoptosis. In this proposal, we will explore two strategies to enhance the efficacy of anti-DRS monoclonal therapy especially in pancreatic tumor cell lines which are intermediate or resistant to anti-DRS. The two strategies are to evaluate the addition of a monoclonal anti-DR4 reagent or the addition of small molecule modulators ofthe apoptosis cascade. The two apoptosis modulators to be evaluated are AT-101, a Bcl-2 family inhibitor, and AT-406, an lAP family inhibitor. These two strategies will be studied using in vitro analysis and orthotopic and metastatic xenogeneic pancreatic cancer models leading to a Phase I trial of the best strategy. In addition, we will continue studies of DDX3 and the DRS/DDX3 complex as a putative biomarker for tumor cell sensitivity/resistance to death receptor mediated anti-tumor efficacy and as the target of enhancement strategies for anti-DR mediated anti-tumor effects.